This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 1. Specific Aims: African-Americans with hypertensive kidney disease have an extremely high prevalence of elevated nocturnal blood pressure (BP). Whether reducing nocturnal BP prevents cardiovascular-renal complications in this population is unknown, as is the feasibility of lowering nocturnal BP. This pilot study is the first step in a long-term research initiative that will determine the role of nocturnal blood pressure reduction as a therapeutic intervention in hypertensive chronic kidney disease. Strategies identified as effective and safe in this pilot study will be used in larger trials to evaluate their effect on clinical end points. The overall goal of this pilot study is to determine the effects of two ramipril based ntihypertensive regimen strategies, each designed to lower nocturnal BP a Specific Aim 1 Determine the effects of each strategy, relative to usual treatment, on nocturnal BP. Specific Aim 2 Determine the effects of each strategy, relative to usual treatment, on clinic BP, daytime BP, 24 hour BP, and dipping status. 2. Background and rationale Elevated nocturnal BP has been associated with adverse renal and cardiovascular outcomes in several observational studies. For example, in the PIUMA study, women who were non-dippers had six fold higher cardiovascular morbidity than dippers (relative risk, 6.79, p0.05).1 In the Syst-Eur study, for every 10% higher night/day ratio of systolic BP, the risk of cardiovascular events was increased by 41% (p=0.03).2 In a small, but provocative retrospective analysis of diabetics, Sturrock et al demonstrated that dippers had a lower mortality than non-dippers (8 vs 26%, p=0.04) and that non-dippers who developed renal insufficiency had the highest mortality (42%).3 Compared to conventional BP measurements, ABPM is more closely associated with the presence and/or magnitude of microalbuminuria. 4,5-7 In addition, patients with a blunted nocturnal decline in BP are more likely to have microalbuminuria. A few small studies have prospectively evaluated the relationship between ABPM and decline in renal function and proteinuria. In a 3 year prospective study, Timio etal demonstrated that the non-dippers had a faster rate of creatinine clearance decline than the dippers (0.37[unreadable] 0.2 vs. 0.27[unreadable] 0.09 ml/min/month;p = 0.002).8 In another study, a significant association was reported between the decline in creatinine clearance over a 24-month period and average nighttime diastolic BP (r = 0.52, p = 0.001) and nocturnal diastolic fall (r = 0.61, p 0.001).9 In a recent prospective study that enrolled 75 young adults with type 1 diabetes with normal urinary albumin excretion and blood pressure, an increase in systolic blood pressure during sleep preceded the development of microalbuminuria. In those whose blood pressure during sleep decreased normally, the progression from normal albumin excretion to microalbuminuria was less likely.10 As described subsequently, cross-sectional data from the AASK cohort study corroborates and extends these observations. The results of these observational studies raise a critical research question, namely, does lowering nocturnal BP reduce the risk of renal and cardiovascular disease? To our knowledge, no trial has addressed this issue, perhaps because there is scant information about interventions that might lower nocturnal BPs. Two trials, one in Europe and one in Japan, have addressed this feasibility issue. In 148 non-dipper hypertensive patients, Hermida et al demonstrated that PM administration of valsartan resulted in the conversion to a dipper profile in 75% of patients while achieving similar 24 hour mean BP reduction compared to AM administration (13/8.5 mmHg in AM vs 14.7/10.3 mmHg in PM).11 Similarly, Kuroda et al compared AM versus PM administration of trandalopril in 37 patients. Reduction in 24 hour mean BP was similar (7.2 mmHg in AM, 5.2 mmHg in PM), but reduction of mean night time BP was higher with the PM administration of trandolapril (11 mm Hg) compared to the AM administration (3.6 mm Hg).12 Other studies have used doxazosin,13-15 nisoldipine, diltiazem or verapamiladministered at bed time. 161718However, these studies did not include African-Americans, patients with chronic kidney disease, or individuals on multiple drug regimens, that is, patients at high risk for cardiovascular-renal outcomes who would be logically the study population in a clinical outcome trial. An ongoing clinical trial study in progress, the Japan Morning Surge-1 (JMS-1), is evaluating whether strict morning blood pressure control by sympathetic nervous system blockade using an alpha-blocker, doxazosin at night time and with the addition of a beta-blocker if needed, can reduce hypertensive target organ damage.19 In the Heart Outcomes Prevention Evaluation (HOPE) study, ramipril was administered at night time as a part of the protocol. This study showed significant reduction in cardiovascular risk in the ramipril group compared to placebo.20 Whether night time blood pressure reduction contributed to reduction in cardiovascular risk cannot be confirmed, but is a reasonable consideration.